Polymers and uses thereof

ABSTRACT

The present invention provides polymers and methods of preparing the same. In certain embodiments, the polymers comprise acrylate repeating units that have been derivatized (e.g., reduced and/or substituted) to form new polymeric structures. In certain embodiments, the polymers described herein self-assemble to form well-defined nanostructures. In some instances, the nanostructures exhibit relatively small d-spacing (e.g., a d-spacing value of 10 nm or less). Due to their properties, the polymers described herein are useful in a variety of applications including functional materials and biomedical applications.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application U.S. Ser.No. 15/875,907, filed Jan. 19, 2018, which claims priority under 35U.S.C. § 119(e) to U.S. Provisional Patent Application, U.S. Ser. No.62/448,475, filed Jan. 20, 2017, the entire contents of each of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

Ordered block copolymers (BCPs), with ultra-small microdomain sizes andrepeat periods, have attracted significant research interest during thepast decades as they find applications in many areas. For example, BCPscan be used as templates for the fabrication of nanowires andbit-patterned storage media, as well as water filtration membranes. See,e.g., Sun et al. “Directed Self-Assembly ofPoly(2-Vinylpyridine)-B-Polystyrene-B-poly(2-Vinylpyridine) TriblockCopolymer with Sub-15 Nm Spacing Line Patterns Using a NanoimprintedPhotoresist Template”, Adv. Mater. 2015, 27 (29), 4364-4370;Thurn-Albrecht et al. “Ultrahigh-Density Nanowire Arrays Grown inSelf-Assembled Diblock Copolymer Templates”, Science 2000, 290 (5499),2126-2129; Kim et al. “Mussel-Inspired Block Copolymer Lithography forLow Surface Energy Materials of Teflon, Graphene, and Gold”, Adv. Mater.2011, 23 (47), 5618-5622; Ruiz et al. “Density Multiplication andImproved Lithography by Directed Block Copolymer Assembly”, Science2008, 321 (5891), 936-939; Jackson et al. “Nanoporous Membranes Derivedfrom Block Copolymers: From Drug Delivery to Water Filtration”, ACSNano. 2010, pp 3548-3553; Peinemann et al. “Asymmetric SuperstructureFormed in a Block Copolymer via Phase Separation”, Nat. Mater. 2007, 6(12), 992-996; Yang, S. Y.; Park, J.; Yoon, J.; Ree, M.; Jang, S. K.;Kim, J. K. Virus Filtration Membranes Prepared from Nanoporous BlockCopolymers with Good Dimensional Stability under High Pressures andExcellent Solvent Resistance. Adv. Funct. Mater. 2008, 18 (9),1371-1377.

To further boost the performance of these materials, achieving smallerfeature sizes/d-spacing (d) is in urgent need. See, e.g., Lo et al.“Silicon-Containing Block Copolymers for Lithographic Applications”,Progress in Polymer Science. 2017; Bates et al. “Block CopolymerLithography”, Macromolecules. 2014, pp 2-12. In particular, achievingsub-10 nm spacing is an important task. See, e.g., Sinturel et al. “Highχ-Low N Block Polymers: How Far Can We Go?”, ACS Macro Letters. 2015, pp1044-1050. To reduce the interdomain spacing of a BCP material, thedegree of polymerization (N) needs to be decreased. This is, however,limited by the fact that the χN value needs to be above a critical value(10.5 for diblock copolymers with conformational symmetry) to maintainthe formation of ordered nanostructures, where x is the Flory-Hugginsinteraction parameter. See, e.g., Bates et al. “CopolymerThermodynamics: Theory and Experiment”, Annu. Rev. Phys. Chem. 1990, 41(1), 525-557. This leads to the general acceptance that the availabilityof high χ-low N block copolymers is the key to the accessibility ofsub-10 nm d-spacing. Note here that, although it has been demonstratedthat by adopting polymer architectures, ordered morphologies can beachieved at slightly lower χN values, it cannot meet the rapid growingrequirement for smaller features. Thus, seeking for BCPs systems withlarge χ values has become one of the major topics in the polymercommunity. See, e.g., Shi et al. “Producing Small Domain Features UsingMiktoarm Block Copolymers with Large Interaction Parameters”, ACS MacroLett. 2015, 4 (11), 1287-1292; Sun et al. “Using Block CopolymerArchitecture to Achieve Sub-10 Nm Periods”, Polym. (United Kingdom)2017, 121, 297-303; Poelma et al. “Cyclic Block Copolymers forControlling Feature Sizes in Block Copolymer Lithography”, ACS Nano2012, 6 (12), 10845-10854; Wang et al. “Block Co-PolyMOCs by StepwiseSelf-Assembly”, J. Am. Chem. Soc. 2016, 138 (33), 10708-10715; Isono etal. “Sub-10 Nm Nano-Organization in AB2- and AB3-Type Miktoarm StarCopolymers Consisting of Maltoheptaose and Polycaprolactone”,Macromolecules 2013, 46 (4), 1461-1469; Olvera de la Cruz et al. “Theoryof Microphase Separation in Graft and Star Copolymers”, Macromolecules1986, 19 (10), 2501-2508.

One popular strategy to this end is the use of strongly interactingadditives. Inorganic salts have been widely used to effectively enhancethe microphase separation in polystyrene-b-poly(ethylene oxide),especially in thin films. See, e.g., Kim et al. “Salt Complexation inBlock Copolymer Thin Films”, Macromolecules 2006, 39 (24), 8473-8479;Epps et al. “Phase Behavior of Lithium Perchlorate-DopedPoly(styrene-B-Isoprene-B-Ethylene Oxide) Triblock Copolymers”, Chem.Mater. 2002, 14 (4), 1706-1714; Park et al. “Macroscopic10-Terabit-per-Square-Inch Arrays from Block Copolymers with LateralOrder. Science 2009, 323 (5917), 1030-1033; Young et al. “Salt Doping inPEO-Containing Block Copolymers: Counterion and Concentration Effects”,Macromolecules 2009, 42 (7), 2672-2678; Teran et al. “Thermodynamics ofBlock Copolymers with and without Salt. J. Phys. Chem. B 2014, 118 (1),4-17. This can also be applied to other coordinating polymers, such aspoly(vinylpyridine)s. Watkins et al. utilized the hydrogen bondingbetween poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethyleneoxide) and polyacrylic acid to form well-ordered polymer blend melts,which displayed d-spacing values around 10 nm. See, e.g., Tirumala etal. “Well Ordered Polymer Melts from Blends of Disordered TriblockCopolymer Surfactants and Functional Homopolymers”, Adv. Mater. 2008, 20(9), 1603-1608. Despite being a useful and effective strategy, itcertainly limits the following processing conditions that can be used,as well as the compatibility with certain applications.

Thus, researchers are motivated to look for BCPs that have intrinsicallyhigher χ values. A few strides have been made towards achieving sub-10nm spacing by selectively pairing traditional polymers. Pionnering workby Hillmyer et al. provided d=20 nm and further suggested that achievingsub-7 nm periodicity is possible, when using block copolymers based onpoly(lactic acid) and polydimethylsiloxane. See, e.g., Rodwogin et al.“Polylactide-Poly(dimethylsiloxane)-Polylactide Triblock Copolymers asMultifunctional Materials for Nanolithographic Applications”, In ACSNano; 2010; Vol. 4, pp 725-732. In 2014, Gopalan et al. successfullyaccessed 9.6 nm periodicity in bulk lamellar morphology based onpoly(tert-butylstyrene)-b-poly(2-vinylpyridine), while the Bates andHillmyer research groups synthesizedpoly(cyclohexylethylene)-b-poly(methyl methacrylate) by hydrogenatingpolystyrene followed by chain extension, which exhibited a 9.0 nmspacing between ordered lamellae in bulk. See, e.g., Sweat et al.“Rational Design of a Block Copolymer with a High InteractionParameter”, Macromolecules 2014, 47 (19), 6687-6696; Kennemur et al.“Sub-5 Nm Domains in Ordered Poly(cyclohexylethylene)-Block-Poly(methylMethacrylate) Block Polymers for Lithography”, Macromolecules 2014, 47(4), 1411-1418. A year later, using a similar strategy, Hillmyer et al.reported poly(cyclohexylethylene)-b-poly(ethylene oxide) with thesmallest spacing being 7.9 nm. See, e.g., Schulze et al.“Poly(cyclohexylethylene)-Block-Poly(ethylene Oxide) Block Polymers forMetal Oxide Templating”, ACS Macro Lett. 2015, 4 (9), 1027-1032.Contemporarily, a lamellar spacing of 8.7 nm based onpoly(dimethylsiloxane)-b-poly(methyl methacrylate) was obtained by theHawker research group. See, e.g., Luo et al.“Poly(dimethylsiloxane-B-Methyl Methacrylate): A Promising Candidate forSub-10 nm Patterning”, Macromolecules 2015, 48 (11), 3422-3430. Progresshas also been achieved by incorporating novel monomers/polymers. It wasreported that the minimum spacing exhibited by the lamellae ofpoly(3-hydroxystyrene)-b-poly(tert-butylstyrene) was as small as 8.8 nm.In case of oligosaccharide-b-poly(para-trimethylsilylstyrene), thesmallest spacing, 8.3 nm, was observed on a cylindrical morphology, inspite of the costly multistep synthesis. See, e.g., Cushen et al.“Oligosaccharide/silicon-Containing Block Copolymers with 5 Nm Featuresfor Lithographic Applications”, ACS Nano 2012, 6 (4), 3424-3433. Bysynthesizing discrete dimethylsiloxanelactic acid diblock co-oligomers,Meijer obtained 6.8 nm and 6.5 nm d-spacing values for lamellar andcylindrical morphologies, respectively. See, e.g., Van Genabeek et al.“Synthesis and Self-Assembly of Discrete Dimethylsiloxane-Lactic AcidDiblock Co-Oligomers: The Dononacontamer and Its Shorter Homologues”, J.Am. Chem. Soc. 2016, 138 (12), 4210-4218. Recently, the Rzayev andRussell groups showcased that 5.4 nm full pitch lamellar domains can berealized by in-situ hydrolyzing poly(solketalmethacrylate)-b-polystyrene into poly(glycerolmonomethacrylate)-b-polystyrene. However, the processing conditions arelimited to acid vapor annealing. See, e.g., Jeong et al. “Realizing 5.4Nm Full Pitch Lamellar Microdomains by a Solid-State Transformation”,Macromolecules 2017, acs.macromol.7b01443 Assisted by highly toxic BBr₃,Kim et al synthesized poly(3,4-dihydroxystyrene)-b-polystyrene and wereable to access 5.9 nm d-spacing in lamellae. See, e.g., Kwak et al.“Fabrication of Sub-3 Nm Feature Size Based on Block CopolymerSelf-Assembly for Next-Generation Nanolithography”, Macromolecules 2017,50 (17), 6813-6818.

Although progress has been achieved recently, the involvement of exoticmonomers, highly toxic reagents, and multistep synthesis limits theirapplications.

SUMMARY OF THE INVENTION

The present invention provides polymers and methods of preparing thesame. The present invention also provides compositions and materialscomprising the polymers described herein. In certain embodiments, thepolymers described herein self-assemble to form well-definednanostructures. In some instances, the nanostructures exhibit relativelysmall d-spacing (e.g., a d-spacing value of 10 nm or less). Smalld-spacing can lead to more well-defined nanostructures and betterperformance of materials. Due to their properties (e.g., the ability toself-organize into well-defined nanostructures), the polymers describedherein are useful in a variety of applications, including functionalmaterials and biomedical applications (e.g., drug delivery systems,nanowires, bit-patterned storage media, filtration membranes, batteries,and more). In certain embodiments, the polymers are formed fromderivatization of polymers (e.g., homopolymers, copolymers, blockcopolymers) comprising acrylate repeating units.

In one aspect, provided herein are polymers comprising repeating unitsof the following formula:

wherein R¹, R², R³ and R^(A) are as defined herein.

For example, in certain embodiments, the polymer comprises a repeatingunit of the following formula:

In certain embodiments, the repeating unit is not of the followingformula:

In certain embodiments, the polymer is a block copolymer. In certainembodiments, at least one of the polymer blocks of the block copolymercomprises repeating units of the following formula:

In certain embodiments, the block copolymer is a diblock copolymer. Incertain embodiments, the block copolymer is a triblock or tetrablockcopolymer. In certain embodiments, the block copolymer comprises five ormore polymer blocks. The additional polymer blocks of the blockcopolymer described herein can be composed of any polymeric material(e.g., composed of any monomers). Examples of classes of polymers areprovided herein.

For example, in certain embodiments, a block copolymer provided hereinis of Formula (I):

wherein T¹, T², R^(A), R¹, R², R³ R⁵, R⁶, R⁷, R⁸, n, and m are asdefined herein.

In certain embodiments, a block copolymer is of Formula (II):

wherein T¹, T², R^(A), R¹, R², R³ R⁵, R⁶, R⁷, R⁸, R^(O), n, and m are asdefined herein.

In certain embodiments, a block copolymer is of the formula:

T¹, T², R^(A), R¹, R², R³ R⁵, R⁶, R⁷, R⁸, R^(O), R^(8a), p, n, whereinand m are as defined herein.

As described above, another aspect of the present invention providesmethods for preparing the polymers provided herein. These methods mayinvolve assembling a homopolymer or copolymer via polymerization,followed by derivatization (e.g., reduction, substitution, etc.).

The details of certain embodiments of the invention are set forth in theDetailed Description of Certain Embodiments, as described below. Otherfeatures, objects, and advantages of the invention will be apparent fromthe Definitions, Examples, Figures, and Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions, p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³Cor ¹⁴C are within the scope of the disclosure. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., CF₃, Bn).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). Examples of haloalkyl groupsinclude —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzo-thienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl. Exemplary 5-membered heteroarylgroups containing 1 heteroatom include, without limitation, pyrrolyl,furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groupscontaining 2 heteroatoms include, without limitation, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary5-membered heteroaryl groups containing 3 heteroatoms include, withoutlimitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary5-membered heteroaryl groups containing 4 heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining 1 heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include,without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary6-membered heteroaryl groups containing 3 or 4 heteroatoms include,without limitation, triazinyl and tetrazinyl, respectively. Exemplary7-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclicheteroaryl groups include, without limitation, indolyl, isoindolyl,indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl,benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclicheteroaryl groups include, without limitation, naphthyridinyl,pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl,phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groupsinclude, without limitation, phenanthridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moietythat includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a doubleor triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa)—, —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl,heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminalR^(dd) substituents can be joined to form ═O or ═S; wherein X⁻ is acounterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(f)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

In certain embodiments, carbon atom substituents include: halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻,—NH₃+X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(═NH)NH(C₁₋₆ alkyl),—OC(═NH)NH₂, —NHC(═NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂(C₁₋₆ alkyl),—SO₂O(C₁₋₆ alkyl), —OSO₂(C₁₋₆ alkyl), —SO(C₁₋₆ alkyl), —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆ alkyl, heteroC₂₋₆ alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻,—OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,and —OP(═O)(N(R^(bb)))₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “monosubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith one hydrogen and one group other than hydrogen, and includes groupsselected from —NH(R^(bb)), —NHC(═O)R^(aa), —NHCO₂R^(aa),—NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa),—NHP(═O)(OR^(cc))₂, and —NHP(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb)and R^(cc) are as defined herein, and wherein R^(bb) of the group—NH(R^(bb)) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith two groups other than hydrogen, and includes groups selected from—N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and—NR^(bb)P(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb), and R^(cc) are asdefined herein, with the proviso that the nitrogen atom directlyattached to the parent molecule is not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith three groups, and includes groups selected from —N(R^(bb))₃ and—N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ are as defined herein.

The term “substituted phosphorous” refers to one of the followinggroups: —P(R_(cc))₂, —P(OR_(cc))₂, —P(R_(cc))₃ ⁺X⁻, —P(OR_(cc))₃ ⁺X⁻,—P(R_(cc))₄, —P(OR_(cc))₄, —P(═O)(N(R_(bb))₂)₂, —P(═O)(R_(aa))₂, or—P(═O)(OR_(cc))₂.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —CC(═O)—O—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, and —C(═S)S(R^(X1)),—C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1), —C(═NR^(X1))SR^(X1), and—C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) is hydrogen; halogen; substitutedor unsubstituted hydroxyl; substituted or unsubstituted thiol;substituted or unsubstituted amino; substituted or unsubstituted acyl,cyclic or acyclic, substituted or unsubstituted, branched or unbranchedaliphatic; cyclic or acyclic, substituted or unsubstituted, branched orunbranched heteroaliphatic; cyclic or acyclic, substituted orunsubstituted, branched or unbranched alkyl; cyclic or acyclic,substituted or unsubstituted, branched or unbranched alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- ordi-heteroaliphaticamino, mono- or di-alkylamino, mono- ordi-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two R^(X1) groups taken together form a 5- to6-membered heterocyclic ring. Exemplary acyl groups include aldehydes(—CHO), carboxylic acids (—CO₂H), ketones, acyl halides, esters, amides,imines, carbonates, carbamates, and ureas. Acyl substituents include,but are not limited to, any of the substituents described herein, thatresult in the formation of a stable moiety (e.g., aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl,thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino,heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl,aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like,each of which may or may not be further substituted).

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “silyl” refers to the group —Si(R^(aa))₃, wherein R^(aa) is asdefined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers tothe group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, P₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo) and activated substituted hydroxyl groups (e.g.,—OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein).

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

The polymers described herein include ionic forms and salt forms. Theterm “salt” refers to ionic compounds that result from theneutralization reaction of an acid and a base. A salt is composed of oneor more cations (positively charged ions) and one or more anions(negative ions) so that the salt is electrically neutral (without a netcharge). Salts of the polymers of this disclosure include those derivedfrom inorganic and organic acids and bases. Examples of acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid, or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Othersalts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and aryl sulfonate.

In certain embodiments, the salt is a pharmaceutically acceptable salt.The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisdisclosure include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “polymer” refers to a molecule comprised of two or more (e.g.,10 or more) repeating units which are covalently bonded together. Incertain embodiments, a polymer comprises 10 or more, 50 or more, 100 ormore, 1000 or more, 2000 or more, or 4000 or more repeating units. Incertain embodiments, a polymer comprises more than 4000 repeating units.The repeating units of a polymer are referred to as “monomers.” A“homopolymer” is a polymer that consists of a single repeating monomer.A “copolymer” is a polymer that comprises two or more different monomersubunits. Copolymers include, but are not limited to, random, block,alternating, segmented, linear, branched, grafted, and taperedcopolymers. Polymers may be natural (e.g., naturally occurringpolypeptides), or synthetic (e.g., non-naturally occurring). A polymermay have an overall molecular weight of 50 Da or greater, 100 Da orgreater, 500 Da or greater, 1000 Da or greater, 2000 Da or greater, 5000Da or greater, 10000 Da or greater, 20000 Da or greater, or 50000 Da orgreater.

The term “monomer” refers to a molecule that may be covalently joined toother monomers to form a polymer. The process by which the monomers arecombined to form a polymer is called polymerization. A macromoleculewith a reactive moiety that enables it to act as a monomer is called amacromonomer.

“Block copolymers” are copolymers comprising homopolymer subunits (i.e.,“blocks”) covalently linked together. The blocks of a block copolymerare separated into distinct domains. A “diblock copolymer” is a blockcopolymer comprising two distinct homopolymer domains. A “triblockcopolymer” is a block copolymer comprising three distinct homopolymerdomains, etc. Each distinct homopolymer domain of a block copolymer isof a different polymeric composition (e.g., comprising differentrepeating monomers).

The term “average polydispersity” (PDI) as used herein refers to ameasure of the distribution of molecular size in a mixture, e.g., asdetermined by a chromatographic method, such as gel permeationchromatography or size exclusion chromatography, or through dynamiclight scattering.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which constitute a part of thisspecification, illustrate several embodiments of the invention andtogether with the description, serve to explain the principles of theinvention.

FIG. 1 . GPC traces on the synthesis of PiBOH₂₁-b-PS₁₄,PPOH_(11.7)-b-PS₂₁, and PPOH_(11.7)-b-PtBS_(15.2). The dashed traced arebefore LiAlH₄ reduction, and the solid lines are the final products.

FIG. 2 . SAXS patterns of block copolymers (BCPs) annealed at 179° C.

FIG. 3A. SAXS patterns of PiBOH₈₄-b-PS₅₁. FIG. 3B. SAXS patterns ofPiBOH₁₆-b-PS₁₄. FIGS. 3A-3B. The inset is a representative TEM image,where the scale bar is 100 nm. The star marks denote the scattering peakfrom Kapton tape.

FIG. 4 . Plot of ln d against ln N.

FIG. 5 . SAXS profiles of PPH_(11.7)-b-PS_(14.5),PPOH_(11.7)-b-PtBS_(15.2), PPOH_(8.6)-b-PtBS_(13.8), andPPOH_(11.7)-b-PtBS_(11.3) at 179° C. The stars mark the scattering peakfrom Kapton tape.

FIG. 6 . Synthesis of poly(isobutenyl alcohol) (PiBOH) using atomtransfer radical polymerization (ATRP) of methyl methacrylate andreduction with lithium aluminum hydride (LAH). FIGS. 7-8 . Spectral datafor poly(methyl methacrylate) PMMA and PiBOH.

FIGS. 9-10 . Synthesis of and characterization data for PiBOH-b-PS.

FIGS. 11A-11B. Morphology of thermally annealed (180° C.) PiBOH-b-PS.

FIG. 12 . Derivatization of PiBOH-containing polymers via reaction ofthe —OH groups.

FIG. 13 . Methylation of PiBOH-containing polymer to form a derivatizedpolymer.

FIG. 14 . Arylation of PiBOH-containing polymer to form a derivatizedpolymer.

FIG. 15A-15C. Alternative synthesis of poly(hydroxyl-isobutylene)(PiBOH). Spectral data is also shown.

FIG. 16A-16D. Synthesis of and spectral data for PiBOH-b-PS blockcopolymer.

FIG. 17A-17B. PMMA-b-PS from an alternative RAFT procedure.

FIGS. 18-19 . Exemplary synthesis of PS-b-PiBOH block copolymer.Spectral and analytical data is also shown.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Provided herein are polymers that, in certain embodiments, self-assembleto form well-defined nanostructures. In some instances, thenanostructures exhibit relatively small d-spacing (e.g., a d-spacingvalue of 10 nm or less), which can lead to more well-definednanostructures. Due to their properties, the polymers described hereinare useful in a variety of applications including functional materialsand biomedical applications (e.g., drug delivery systems, nanowires,bit-patterned storage media, filtration membranes, and more). Alsoprovided herein are compositions and materials comprising the polymers,and uses of the polymers.

In certain embodiments, the polymers are prepared from derivatization(e.g., reduction) of polymers (e.g., homopolymers, copolymers, blockcopolymers) comprising acrylate repeating units. Another aspect of thepresent invention provides methods for preparing the polymers providedherein. These methods may involve assembling a homopolymer or copolymer,followed by derivatization (e.g., reduction, substitution, etc.) of theacrylate portions of the polymer.

Polymers

In one aspect, the present invention provides polymers (e.g.,homopolymers, copolymers, block copolymers). In certain embodiments, thepolymers comprise polyacrylate repeating units that have beenderivatized (e.g., reduced, and optionally further derivatized). Forexample, in certain embodiments, the present invention provideshomopolymers or copolymers comprising acrylate repeating units, whereinthe acrylate repeating units have been reduced. In certain embodiments,the acrylate repeating units are not poly(methyl methacrylate) (PMMA)repeating units. The present invention also provides block copolymers(e.g., diblock, triblock, tetrablock copolymers) wherein at least oneblock comprises acrylate repeating units, wherein the acrylate repeatingunits have been reduced. In certain embodiments, the polymers haveuseful properties, such as defined structures after self-assembly. Incertain embodiments, the polymers self-assemble to form specificmorphologies (e.g., lamellar, hexagonal cylinder, body centered cubicmorphology) with certain d-spacing values (e.g., less than 10 nm). Thewell-defined morphologies and relatively small d-spacing values ofpolymers described herein can confer advantageous properties, and thusthe polymers are useful in, e.g., functional materials and biomedicalapplications (e.g., drug delivery systems, nanowires, bit-patternedstorage media, filtration membranes, and more).

Provided herein are polymers comprising repeating units of the followingformula:

wherein:

R¹, R², and R³ are independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R^(A) is halogen, —OR^(O), —SR^(S), —N(R^(N))₂, or substitutedphosphorous;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a nitrogen protecting group;optionally wherein two R^(N) attached to the same nitrogen atom arejoined together with the intervening atoms to form optionallysubstituted heterocyclyl or optionally substituted heteroaryl;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a sulfur protecting group;

provided that the repeating unit is not of the formula:

In certain embodiments, the polymer comprises repeating units of one ofthe following formulae:

In certain embodiments, the polymer comprises repeating units of thefollowing formula:

In certain embodiments, the polymer comprises repeating units of thefollowing formula:

In certain embodiments, the polymer is a reduced form of poly(methylacrylate), comprising repeating units of the following formula:

In certain embodiments, the polymer is a block copolymer. Providedherein are block copolymers, wherein at least one of the polymer blockscomprises repeating units of the following formula:

wherein:

R¹, R², and R³ are independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R^(A) is halogen, —OR^(O), —SR^(S), —N(R^(N))₂, or substitutedphosphorous;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a nitrogen protecting group;optionally wherein two R^(N) attached to the same nitrogen atom arejoined together with the intervening atoms to form optionallysubstituted heterocyclyl or optionally substituted heteroaryl;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a sulfur protecting group.

In certain embodiments, at least one of the polymer blocks of the blockcopolymer comprises repeating units of one of the following formulae:

In certain embodiments, at least one of the polymer blocks of the blockcopolymer comprises repeating units of the following formula:

In certain embodiments, at least one of the polymer blocks of the blockcopolymer comprises repeating units of the following formula:

In certain embodiments, at least one of the polymer blocks of the blockcopolymer comprises repeating units of the following formula:

In certain embodiments, at least one of the polymer blocks of the blockcopolymer comprises repeating units of the following formula:

In certain embodiments, the block copolymer is a diblock copolymer. Incertain embodiments, the block copolymer is a triblock or tetrablockcopolymer. In certain embodiments, the block copolymer comprises five ormore polymer blocks.

The additional polymer blocks of the block copolymer described hereincan be composed of any polymeric material (e.g., any monomers). Examplesof polymers include, but are not limited to, polyvinyl polymers (e.g.,polyvinyl chloride), polyethylenes (e.g., polyethylene,polytetrafluoroethylene), polypropylenes, polyacetylenes, polyethers(e.g., polyethylene glycol, polyoxymethylene, polypropylene glycol,polytetramethylene glycol, poly(ethyl ethylene) phosphate,poly(oxazoline)), polyamines, polyesters (e.g., polyglycolic acid,polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone,polyhydroxyalkanoate, polyhydroxybutryate, polyethylene adipate,polybutylene succinate, poly(3-hydroxybutyrate-co-3-hydroxyvalerate),polysilanes, polysiloxanes (e.g., polydimethylsiloxane), polyacrylates(e.g., polymethacrylate, poly(n-butyl acrylate), poly(tert-butylacrylate)), polystyrenes, polylactides (e.g., polylactic acid),polyamino acids, polypeptides, polyamides, polyacrylamides (e.g.,polymethylacrylamide), and polysaccharides.

For example, in certain embodiments, the block copolymer comprises asecond polymer block, wherein the second polymer block comprisesrepeating units of the formula:

wherein:

R⁵, R⁶, and R⁷ are independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

each instance of R^(8a) is independently hydrogen, halogen, —CN, —NO₂,—N₃, optionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —OR^(O),—SR^(S), or —N(R^(N))₂;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a nitrogen protecting group;optionally wherein two R^(N) attached to the same nitrogen atom arejoined together with the intervening atoms to form optionallysubstituted heterocyclyl or optionally substituted heteroaryl;

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a sulfur protecting group;and

p is 0, 1, 2, 5, 4, or 5.

In certain embodiments, the second polymer block is a polymer composedof optionally substituted styrene monomers. In certain embodiments, thesecond polymer block is polystyrene (PS), poly(4-vinylanisole),poly(4-acetoxystyrene), poly(4-tert-butoxystyrene),poly(4-fluorostyrene), poly(3-nitrostyrene), poly(α-methylstyrene),poly(methylstyrene), or poly(4-tert-butylstyrene).

In certain embodiments, the block copolymer comprises a polystyrene (PS)block, wherein the repeating units of the second polymer block are ofthe formula:

In certain embodiments, the block copolymer comprises apoly(4-tert-butylstyrene) (PtBS) block wherein the repeating units ofthe second polymer block are of the formula:

In certain embodiments, the block copolymers provided herein are ofFormula (I):

wherein:

T¹ and T² are independently terminal groups selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substituted acyl, andpolymers;

R^(A) is halogen, —OR^(O), —SR^(S), —N(R^(N))₂, or substitutedphosphorous;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a nitrogen protecting group;optionally wherein two R^(N) attached to the same nitrogen atom arejoined together with the intervening atoms to form optionallysubstituted heterocyclyl or optionally substituted heteroaryl;

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a sulfur protecting group;and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or a sulfur protecting group

R¹, R², and R³ are independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R⁵, R⁶, and R⁷ are independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R⁸ is optionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substituted acyl; or R⁸is a polymer; and

n and m are independently integers from 1 to 2000, inclusive.

In certain embodiments, the block copolymer is of one of the followingformulae:

In certain embodiments, the block copolymer is of Formula (II):

In certain embodiments, the block copolymer is of Formula (III):

In certain embodiments, the block copolymer is of the formula:

In certain embodiments, the block copolymer is of the formula:

wherein:

each instance of R^(8a) is independently hydrogen, halogen, —CN, —NO₂,—N₃, optionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —OR^(O),—SR^(S), or —N(R^(N))₂; and

p is 0, 1, 2, 5, 4, or 5.

In certain embodiments, the block copolymer is of the formula:

In certain embodiments, the block copolymer is of the formula:

In certain embodiments, the block copolymer is of the formula:

In certain embodiments, the block copolymer is of the formula:

In certain embodiments, the block copolymer is of the formula:

As generally defined herein, n is an integer from 1-2000, inclusive. Incertain embodiments, n is from 2-1000, inclusive. In certainembodiments, n is from 2-200, inclusive. In certain embodiments, n isfrom 2-100, inclusive. In certain embodiments, n is from 2-50,inclusive. In certain embodiments, n is from 2-40, inclusive. In certainembodiments, n is from 2-30, inclusive. In certain embodiments, n isfrom 2-20, inclusive. In certain embodiments, n is from 2-10, inclusive.In certain embodiments, n is from 5-20, inclusive.

As generally defined herein, m is an integer from 1-2000, inclusive. Incertain embodiments, m is from 2-1000, inclusive. In certainembodiments, m is from 2-200, inclusive. In certain embodiments, m isfrom 2-100, inclusive. In certain embodiments, m is from 2-50,inclusive. In certain embodiments, m is from 2-40, inclusive. In certainembodiments, m is from 2-30, inclusive. In certain embodiments, m isfrom 2-20, inclusive. In certain embodiments, m is from 2-10, inclusive.In certain embodiments, m is from 5-20, inclusive.

The ratio of n to m can be any ratio. In certain embodiments, the ratioof n to m is approximately 1:1. In certain embodiments, the ratio of nto m is approximately from 1:1 to 1:2. In certain embodiments, the ratioof n to m is approximately 1:1.1. In certain embodiments, the ratio of nto m is approximately 1:1.2. In certain embodiments, the ratio of n to mis approximately 1:1.3. In certain embodiments, the ratio of n to m isapproximately 1:1.4. In certain embodiments, the ratio of n to m isapproximately 1:1.5. In certain embodiments, the ratio of n to m isapproximately 1:1.6. In certain embodiments, the ratio of n to m isapproximately 1:1.7. In certain embodiments, the ratio of n to m isapproximately 1:1.8. In certain embodiments, the ratio of n to m isapproximately 1:1.9. In certain embodiments, the ratio of n to m isapproximately 1:2.0.

In certain embodiments, the ratio of m to n is approximately from 1:1 to1:2. In certain embodiments, the ratio of m to n is approximately 1:1.1.In certain embodiments, the ratio of m to n is approximately 1:1.2. Incertain embodiments, the ratio of m to n is approximately 1:1.3. Incertain embodiments, the ratio of m to n is approximately 1:1.4. Incertain embodiments, the ratio of m to n is approximately 1:1.5. Incertain embodiments, the ratio of m to n is approximately 1:1.6. Incertain embodiments, the ratio of m to n is approximately 1:1.7. Incertain embodiments, the ratio of m to n is approximately 1:1.8. Incertain embodiments, the ratio of m to n is approximately 1:1.9. Incertain embodiments, the ratio of m to n is approximately 1:2.0.

The polymers described herein may self-assemble into form structureswith any morphology. In certain embodiments, the polymers self-assembleinto structures with hexagonal cylindrical, gyroid, spherical, lamellar,ellipsoidal, polyhedral, or cubic morphologies. In certain embodiments,the polymer has a lamellae, hexagonal cylinder, or body-centered cubicmorphology.

Self-assembled polymers described herein have d-spacing values which canbe measured. “d-spacing,” as used herein, refers to the spacing ordistance between successive planes of atoms in an ordered nanostructure.In certain embodiments, the d-spacing value is from 1-50 nm. In certainembodiments, the d-spacing value is from 1-40 nm. In certainembodiments, the d-spacing value is from 1-30 nm. In certainembodiments, the d-spacing value is from 1-20 nm. In certainembodiments, the d-spacing value is less than 20 nm. In certainembodiments, the d-spacing value is less than 25 nm. In certainembodiments, the d-spacing value is less than 24 nm. In certainembodiments, the d-spacing value is less than 23 nm. In certainembodiments, the d-spacing value is less than 22 nm. In certainembodiments, the d-spacing value is less than 21 nm. In certainembodiments, the d-spacing value is less than 20 nm. In certainembodiments, the d-spacing value is less than 19 nm. In certainembodiments, the d-spacing value is less than 18 nm. In certainembodiments, the d-spacing value is less than 17 nm. In certainembodiments, the d-spacing value is less than 16 nm. In certainembodiments, the d-spacing value is less than 15 nm. In certainembodiments, the d-spacing value is less than 14 nm. In certainembodiments, the d-spacing value is less than 13 nm. In certainembodiments, the d-spacing value is less than 12 nm. In certainembodiments, the d-spacing value is less than 11 nm. In certainembodiments, the d-spacing value is less than 10 nm. In certainembodiments, the d-spacing value from 1-10 nm. In certain embodiments,the d-spacing value from 5-10 nm. In certain embodiments, the d-spacingvalue is less than 9 nm. In certain embodiments, the d-spacing value isless than 8 nm. In certain embodiments, the d-spacing value is less than7 nm. In certain embodiments, the d-spacing value is less than 6 nm. Incertain embodiments, the d-spacing value is less than 5 nm. In apreferred embodiment, the d-spacing value is less than 10 nm.

Polymers described herein may be of any molecular weight. A polymer mayhave an overall molecular weight of approximately 10 Da or greater,approximately 20 Da or greater, approximately 30 Da or greater,approximately 50 Da or greater, approximately 100 Da or greater,approximately 500 Da or greater, approximately 1000 Da or greater,approximately 2000 Da or greater, approximately 5000 Da or greater,approximately 10000 Da or greater, approximately 20000 Da or greater, orapproximately 50000 Da or greater.

The following R group definitions apply to all polymers, compounds, andmethods described herein.

As generally defined herein, R^(A) is halogen, —OR^(O), —SR^(S),—N(R^(N))₂, or substituted phosphorous. In certain embodiments, R^(A) ishalogen (e.g., —Cl, —F, —Br, —I). In certain embodiments, R^(A) is—OR^(O). In certain embodiments, R^(A) is —SR^(S). In certainembodiments, R^(A) is —N(R^(N))₂. In certain embodiments, R^(A) issubstituted phosphorous (e.g., —P(R_(cc))₂, —P(OR_(cc))₂, —P(R_(cc))₃⁺X⁻, —P(OR_(cc))₃ ⁺X⁻, —P(R_(cc))₄, —P(OR_(cc))₄, —P(═O)(N(R_(bb))₂)₂,—P(═O)(R_(aa))₂, or —P(═O)(OR_(cc))₂).

As generally defined herein, R¹ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R¹ is hydrogen. Incertain embodiments, R¹ is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R¹ is optionally substituted alkyl. In certain embodiments,R¹ is optionally substituted aryl. In certain embodiments, R¹ isoptionally substituted heteroaryl. In certain embodiments, R¹ isoptionally substituted carbocyclyl. In certain embodiments, R¹ isoptionally substituted heterocyclyl. In certain embodiments, R¹ isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R¹ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R¹ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R¹ is unsubstituted C₁₋₃alkyl. In certain embodiments, R¹ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R¹ is methyl.

As generally defined herein, R² is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R² is hydrogen. Incertain embodiments, R² is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R² is optionally substituted alkyl. In certain embodiments,R² is optionally substituted aryl. In certain embodiments, R² isoptionally substituted heteroaryl. In certain embodiments, R² isoptionally substituted carbocyclyl. In certain embodiments, R² isoptionally substituted heterocyclyl. In certain embodiments, R² isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R² isunsubstituted C₁₋₆ alkyl. In certain embodiments, R² is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R² is unsubstituted C₁₋₃alkyl. In certain embodiments, R² is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R² is methyl.

As generally defined herein, R³ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R³ is hydrogen. Incertain embodiments, R³ is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R³ is optionally substituted alkyl. In certain embodiments,R³ is optionally substituted aryl. In certain embodiments, R³ isoptionally substituted heteroaryl. In certain embodiments, R³ isoptionally substituted carbocyclyl. In certain embodiments, R³ isoptionally substituted heterocyclyl. In certain embodiments, R³ isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R³ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R³ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R³ is unsubstituted C₁₋₃alkyl. In certain embodiments, R³ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R³ is methyl.

In certain embodiments, R¹, R², and R³ are each hydrogen. In certainembodiments, R and R² are hydrogen; and R³ is methyl. In certainembodiments, R³ is not methyl.

As generally defined herein, R⁵ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R⁵ is hydrogen. Incertain embodiments, R⁵ is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R⁵ is optionally substituted alkyl. In certain embodiments,R⁵ is optionally substituted aryl. In certain embodiments, R⁵ isoptionally substituted heteroaryl. In certain embodiments, R⁵ isoptionally substituted carbocyclyl. In certain embodiments, R⁵ isoptionally substituted heterocyclyl. In certain embodiments, R⁵ isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R⁵ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R⁵ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R⁵ is unsubstituted C₁₋₃alkyl. In certain embodiments, R⁵ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R⁵ is methyl.

As generally defined herein, R⁶ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R⁶ is hydrogen. Incertain embodiments, R⁶ is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R⁶ is optionally substituted alkyl. In certain embodiments,R⁶ is optionally substituted aryl. In certain embodiments, R⁶ isoptionally substituted heteroaryl. In certain embodiments, R⁶ isoptionally substituted carbocyclyl. In certain embodiments, R⁶ isoptionally substituted heterocyclyl. In certain embodiments, R⁶ isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R⁶ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R⁶ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R⁶ is unsubstituted C₁₋₃alkyl. In certain embodiments, R⁶ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R⁶ is methyl.

As generally defined herein, R⁷ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbocyclyl, or optionallysubstituted heterocyclyl. In certain embodiments, R⁷ is hydrogen. Incertain embodiments, R⁷ is halogen (e.g., —Cl, —F, —Br, —I). In certainembodiments, R⁷ is optionally substituted alkyl. In certain embodiments,R⁷ is optionally substituted aryl. In certain embodiments, R⁷ isoptionally substituted heteroaryl. In certain embodiments, R⁷ isoptionally substituted carbocyclyl. In certain embodiments, R⁷ isoptionally substituted heterocyclyl. In certain embodiments, R⁷ isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R⁷ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R⁷ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R⁷ is unsubstituted C₁₋₃alkyl. In certain embodiments, R⁷ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R⁷ is methyl.

In certain embodiments, R⁵, R⁶, and R⁷ are each hydrogen.

As generally defined herein, R⁸ is optionally substituted alkyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted acyl; or R⁸ is a polymer. In certain embodiments,R⁸ is optionally substituted alkyl. In certain embodiments, R⁸ isoptionally substituted carbocyclyl. In certain embodiments, R⁸ isoptionally substituted heterocyclyl. In certain embodiments, R⁸ isoptionally substituted aryl. In certain embodiments, R⁸ is optionallysubstituted heteroaryl. In certain embodiments, R⁸ is optionallysubstituted acyl. In certain embodiments, R⁸ is a polymer sidechain. Incertain embodiments, R⁸ is optionally substituted phenyl. In certainembodiments, R⁸ is of the formula:

In certain embodiments, R⁸ is of one of the following formulae:

In certain embodiments, R⁸ is of the formula:

In certain embodiments, R⁸ is of the formula:

In certain embodiments, R⁸ is of the formula:

As defined herein, each instance of R^(8a) is independently hydrogen,halogen, —CN, —NO₂, —N₃, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, —OR^(O), —SR^(S), or —N(R^(N))₂. In certainembodiments, at least one instance of R^(8a) is hydrogen. In certainembodiments, at least one instance of R^(8a) is halogen. In certainembodiments, at least one instance of R^(8a) is —CN. In certainembodiments, at least one instance of R^(8a) is —NO₂. In certainembodiments, at least one instance of R^(8a) is —N₃. In certainembodiments, at least one instance of R^(8a) is optionally substitutedalkyl. In certain embodiments, at least one instance of R^(8a) isoptionally substituted carbocyclyl. In certain embodiments, at least oneinstance of R^(8a) is optionally substituted heterocyclyl. In certainembodiments, at least one instance of R^(8a) is optionally substitutedaryl. In certain embodiments, at least one instance of R^(8a) isoptionally substituted heteroaryl. In certain embodiments, at least oneinstance of R^(8a) is optionally substituted acyl. In certainembodiments, at least one instance of R^(8a) is —OR^(O). In certainembodiments, at least one instance of R^(8a) is —SR^(S). In certainembodiments, at least one instance of R^(8a) is —N(R^(N))₂. In certainembodiments, at least one instance of R^(8a) is unsubstituted C₁₋₆alkyl. In certain embodiments, at least one instance of R^(8a) isoptionally substituted C₁₋₃ alkyl. In certain embodiments, at least oneinstance of R^(8a) is unsubstituted C₁₋₃ alkyl. In certain embodiments,at least one instance of R^(8a) is selected from the group consisting ofmethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, andtert-butyl. In certain embodiments, at least one instance of R^(8a) istert-butyl.

As generally defined herein, p is 0, 1, 2, 3, 4, or 5. In certainembodiments, p is 0. In certain embodiments, p is 1. In certainembodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4. In certain embodiments, p is 5.

As generally defined herein, T¹ is a terminal group selected from thegroup consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substituted acyl, andpolymers. In certain embodiments, T¹ is hydrogen. In certainembodiments, T¹ is halogen. In certain embodiments, T¹ is optionallysubstituted alkyl. In certain embodiments, T¹ is optionally substitutedalkenyl. In certain embodiments, T¹ is optionally substituted alkynyl.In certain embodiments, T¹ is optionally substituted heteroalkyl. Incertain embodiments, T¹ is optionally substituted carbocyclyl. Incertain embodiments, T¹ is optionally substituted heterocyclyl. Incertain embodiments, T¹ is optionally substituted aryl. In certainembodiments, T¹ is optionally substituted heteroaryl. In certainembodiments, T¹ is and optionally substituted acyl. In certainembodiments, T¹ is optionally substituted C₁₋₆ alkyl. In certainembodiments, T¹ is of one of the following formulae:

As generally defined herein, T² is a terminal group selected from thegroup consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substituted acyl, andpolymers. In certain embodiments, T² is hydrogen. In certainembodiments, T² is halogen. In certain embodiments, T² is optionallysubstituted alkyl. In certain embodiments, T² is optionally substitutedalkenyl. In certain embodiments, T² is optionally substituted alkynyl.In certain embodiments, T² is optionally substituted heteroalkyl. Incertain embodiments, T² is optionally substituted carbocyclyl. Incertain embodiments, T² is optionally substituted heterocyclyl. Incertain embodiments, T² is optionally substituted aryl. In certainembodiments, T² is optionally substituted heteroaryl. In certainembodiments, T² is and optionally substituted acyl. In certainembodiments, T² is optionally substituted C₁₋₆ alkyl. In certainembodiments, T² is of one of the following formulae:

As generally defined herein, R^(O) hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted acyl, or an oxygen protecting group. In certainembodiments, R^(O) is hydrogen. In certain embodiments, R^(O) isoptionally substituted alkyl. In certain embodiments, R^(O) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R^(O) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(O) is selected fromthe group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, and tert-butyl. In certain embodiments, R^(O) ismethyl. In certain embodiments, R^(O) is optionally substituted aryl. Incertain embodiments, R^(O) is optionally substituted heteroaryl. Incertain embodiments, R^(O) is optionally substituted carbocyclyl. Incertain embodiments, R^(O) is optionally substituted heterocyclyl. Incertain embodiments, R^(O) is optionally substituted acyl. In certainembodiments, R^(O) is an oxygen protecting group.

As generally defined herein, each instance of R^(N) is independentlyhydrogen, optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, ora nitrogen protecting group; or optionally two R^(N) on the samenitrogen atom are taken together with the intervening atoms to formoptionally substituted heterocyclyl or optionally substitutedheteroaryl. In certain embodiments, R^(N) is hydrogen. In certainembodiments, R^(N) is optionally substituted alkyl. In certainembodiments, R^(N) is optionally substituted C₁₋₆ alkyl. In certainembodiments, R^(N) is unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(N) is optionally substituted C₁₋₃ alkyl. In certain embodiments,R^(N) is unsubstituted C₁₋₃ alkyl. In certain embodiments, R^(N) isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. In certainembodiments, R^(N) is optionally substituted carbocyclyl. In certainembodiments, R^(N) is optionally substituted heterocyclyl. In certainembodiments, R^(N) is optionally substituted aryl. In certainembodiments, R^(N) is optionally substituted heteroaryl. In certainembodiments, R^(N) is or a nitrogen protecting group. In certainembodiments, R^(N) on the same nitrogen atom are taken together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl.

As generally defined herein, R^(S) hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted acyl, or a sulfur protecting group. In certainembodiments, R^(S) is hydrogen. In certain embodiments, R^(S) isoptionally substituted alkyl. In certain embodiments, R^(S) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, R^(S) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(S) is selected fromthe group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, and tert-butyl. In certain embodiments, R^(S) ismethyl. In certain embodiments, R^(S) is optionally substituted aryl. Incertain embodiments, R^(S) is optionally substituted heteroaryl. Incertain embodiments, R^(S) is optionally substituted carbocyclyl. Incertain embodiments, R^(S) is optionally substituted heterocyclyl. Incertain embodiments, R^(S) is optionally substituted acyl. In certainembodiments, R^(S) is a sulfur protecting group.

Uses and Compositions

Polymers described herein can be used in material and biomedicalapplications. For example, polymers described herein can be used infunctional materials such as photonics (e.g., photonic crystals),chromatography media (e.g., filtration membranes), stimuli-responsivematerials, lubricants, coatings, nanowires, nanolithography, storagemedia, films, and batteries (e.g., lithium-air batteries). Polymersdescribed herein are also useful in biomedical applications such as drugdelivery, materials (e.g., an injectable implant) for tissue orcartilage repair, cosmetic implantation, and lubrication of tissues orbiological membranes.

Also provided herein are compositions comprising a polymer describedherein and one or more carriers. The carrier may be a pharmaceuticallyacceptable carrier or another chemical medium (e.g., a solvent or othermedium). In certain embodiments, the composition is a pharmaceuticalcompostion optionally comprising one or more additional agents (e.g.,therapeutic agents)

Also provided herein are particles (e.g., nanoparticles, microparticles)comprising a polymer described herein. In another aspect, the presentinvention provides gels (e.g., hydrogels) comprising polymers describedherein.

Also provided herein are kits comprising one or more polymers describedherein, or a composition or material thereof. The kit may furthercomprise instructions for use of the polymer, composition, or material.

Methods for Preparing Polymers

Provided herein are methods for preparing the polymers described herein.In general, the methods comprise polymerizing one or more monomers toform a homopolymer or copolymer, wherein at least one of the monomers isan acrylate. The polyacrylate portions of the homopolymer or copolymercan then be reduced to form polymeric segments with hydroxyl sidechains.The hydroxyl groups of the resulting polymer can then be reacted (e.g.,substituted or protected) to form a derivatized polymer. This process isoutlined in Scheme A.

Provided herein is a method for preparing a polymer, the methodcomprising reducing an original polymer; wherein the original polymercomprises polyacrylate repeating units. In certain embodiments, thepolyacrylate repeating units are not poly(methyl methacrylate) repeatingunits. The acrylate repeating units of the original polymer may be fullyor partially reduced. In certain embodiments, the acrylate repeatingunits are approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% reduced.

In certain embodiments, the polyacrylate repeating units of the originalpolymer are of the formula:

and the polyacrylate repeating units of the original polymer are reducedto form a polymer with repeating units of the formula:

wherein:

R⁴ is hydrogen, optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, oran oxygen protecting group.

As generally defined herein, R⁴ is hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted acyl, or an oxygen protecting group. In certainembodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is optionallysubstituted alkyl. In certain embodiments, R⁴ is optionally substitutedaryl. In certain embodiments, R⁴ is optionally substituted heteroaryl.In certain embodiments, R⁴ is optionally substituted carbocyclyl. Incertain embodiments, R⁴ is optionally substituted heterocyclyl. Incertain embodiments, R⁴ is optionally substituted acyl. In certainembodiments, R⁴ is an oxygen protecting group. In certain embodiments,R⁴ is optionally substituted C₁₋₆ alkyl. In certain embodiments, R⁴ isunsubstituted C₁₋₆ alkyl. In certain embodiments, R⁴ is optionallysubstituted C₁₋₃ alkyl. In certain embodiments, R⁴ is unsubstituted C₁₋₃alkyl. In certain embodiments, R⁴ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In certain embodiments, R⁴ is methyl.

In certain embodiments, the method further comprises a step of reactingthe —OH groups of the repeating units to form repeating units of theformula:

In certain embodiments, the —OH groups are protected (e.g., alkylated,arylated, heteroarylated) to transform the —OH groups to groups of theformula —OR^(O). In certain embodiments, the —OH groups are substituted(e.g., transformed into a leaving group and then treated with anucleophile) to transform the —OH groups to groups of the formula—R^(A). Non-limiting examples of protection and substitution reactionsof this kind are outlined in the Figures.

As described above, in certain embodiments, a polymer provided herein isa block copolymer. Therefore, provided herein is a method of preparing ablock copolymer, the method comprising reducing an original blockcopolymer, wherein the original block copolymer is of the formula:

to yield a block copolymer of the formula:

The acrylate repeating units of the original block copolymer may befully or partially reduced. In certain embodiments, the acrylaterepeating units are approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% reduced.

In certain embodiments, the original block copolymer is of the formula:

In certain embodiments, the original block copolymer is of the formula:

In certain embodiments, the method further comprises a step of reactingthe —OH groups of the block copolymer to form a block copolymer of theformula:

As described above, in certain embodiments, the —OH groups are protected(e.g., alkylated, arylated, heteroarylated) to transform the —OH groupsto groups of the formula —OR^(O). In certain embodiments, the —OH groupsare substituted (e.g., transformed into a leaving group and then treatedwith a nucleophile) to transform the —OH groups to groups of the formula—R^(A). Non-limiting examples of protection and substitution reactionsof this kind are outlined in the Figures.

In certain embodiments, the step of reducing (i.e., the step of reducinga group of the formula —CO₂R⁴ to a group of the formula —CH₂OH) iscarried out in the presence of a reducing agent. In certain embodiments,the reduction is carried out in the presence of one or more of lithiumaluminum hydride, hydrogen gas, sodium amalgam, sodium-lead alloy,diborane, sodium borohydride, dithionates, thiosulfates, hydrazine,diisobutylaluminium hydride (DIBAL), oxalic acid, formic acid, ascorbicacid, lithium triethylborohydride, diborane, borane-tetrahydrofuran,borane-dimethyl sulfide, samarium, sodium bis(2-methoxyethoxy)aluminiumhydride, sodium triacetoxyborohydride, or zinc.

In certain embodiments, the reduction is carried out in the presence ofa hydride donor. In certain embodiments, the hydride donor isdiisobutylaluminium hydride (DIBAL) or lithium aluminum hydride (LAH).In certain embodiments, the hydride donor is LAH.

The methods described herein may further comprise one or morepolymerization steps in order to prepare an original homopolymer orcopolymer. For instance, in certain embodiments, the methods may furthercomprise steps of polymerizing two or more monomers to produce theoriginal polymer or block copolymer, wherein at least one monomer is anacrylate of the formula:

In certain embodiments, the monomer is not poly(methyl methacrylate)(PMMA).

In certain embodiments, the polymerization step is a polymerizationselected from the group consisting of living radical polymerization,reversible-deactivation radical polymerization, atom transfer radicalpolymerization (ATRP), nitroxide mediated radical polymerization (NMP),and reversible addition-fragmentation chain transfer (RAFT)polymerization.

In certain embodiments, the polymerization uses an iniferter, initiator,or chain transfer agent. The term“iniferter” refers to a chemicalcompound that simultaneously acts as a initiator, transfer agent, andterminator. The term “initiator” refers to a chemical compound that canproduce radical species and/or promote radical reactions. The term“chain transfer agent” refers to a a chemical compound that is able toreact with a chain carrier by a reaction in which the original chaincarrier is deactivated and a new chain carrier is generated. In certainembodiments, the iniferter, initiator, or chain transfer agent isselected from the group consisting of dithiobenzoates,trithiocarbonates, dithiocarbamates, xanthates, and alkyl halides.

Examples of dithiobenzoate include, but are not limited to, benzylbenzodithioate, cyanomethyl benzodithioate,4-cyano-4-(phenylcarbonothioylthio)pentanoic acid,4-cyano-4-(phenylcarbonothioylthio)pentanoic acid N-succinimidyl ester,2-cyano-2-propyl benzodithioate, 2-cyano-2-propyl 4-cyanobenzodithioate,ethyl 2-(4-methoxyphenylcarbonothioylthio)acetate, ethyl2-methyl-2-(phenylthiocarbonylthio)propionate, ethyl2-(phenylcarbonothioylthio)-2-phenylacetate, ethyl2-(phenylcarbonothioylthio)propionate, 1-(methoxycarbonyl)ethylbenzodithioate, 2-(4-methoxyphenylcarbonothioylthio)ethanoic acid,2-nitro-5-(2-propynyloxy)benzyl4-cyano-4-(phenylcarbonothioylthio)pentanoate,2-(phenylcarbonothioylthio)propanoic acid, and 2-phenyl-2-propylbenzodithioate.

Examples of trithiocarbonates include, but are not limitedto,3,5-bis(2-dodecylthiocarbonothioylthio-1-oxopropoxy)benzoic acid,2-cyanobutan-2-yl 4-chloro-3,5-dimethyl-1H-pyrazole-1-carbodithioate,2-cyanobutanyl-2-yl 3,5-dimethyl-1H-pyrazole-1-carbodithioate,4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid,4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanol, cyanomethyl(3,5-dimethyl-1H-pyrazole)-carbodithioate, cyanomethyl dodecyltrithiocarbonate, cyanomethyl[3-(trimethoxysilyl)propyl]trithiocarbonate, 2-cyano-2-propyl dodecyltrithiocarbonate, S,S-dibenzyl trithiocarbonate,2-(dodecylthiocarbonothioylthio)propionic acid,2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid3-azido-1-propanol ester,2-(dodecylthiocarbonothioylthio)-2-methylpropionic acidN-hydroxysuccinimide ester,2-(dodecylthiocarbonothioylthio)-2-methylpropionic acidpentafluorophenyl ester, phthalimidomethyl butyl trithiocarbonate,methyl 2-(dodecylthiocarbonothioylthio)-2-methylpropionate,2,2′-(thiocarbonylbis(sulfanediyl))bis(2-methylpropanoic acid), dibenzyl2,2′-(thiocarbonylbis(sulfanediyl))bis(2-methylpropanoate), dibenzyl2,2′-(thiocarbonylbis(sulfanediyl))dipropionate, and2-(((dodecylthio)carbonothioyl)thio)propanoic acid.

Examples of dithiocarbamates include, but are not limited to, benzyl1H-pyrrole-1-carbodithioate, cyanomethyl diphenylcarbamodithioate,cyanomethyl methyl(phenyl)carbamodithioate, cyanomethylmethyl(4-pyridyl)carbamodithioate, 2-cyanopropan-2-ylN-methyl-N-(pyridin-4-yl)carbamodithioate, methyl2-[methyl(4-pyridinyl)carbamothioylthio]propionate, and1-succinimidyl-4-cyano-4-[N-methyl-N-(4-pyridyl)carbamothioylthio]pentanoate.Examples of xanthates include, but are not limited to, ethyl2-(((ethylthio)carbonothioyl)thio)propanoate, methyl(4-methoxyphenoxy)carbonothioylsulfanyl acetate, methyl(methoxycarbonothioyl)sulfanyl acetate, methyl(ethoxycarbonothioyl)sulfanyl acetate, and methyl(isopropoxycarbonothioyl)sulfanyl acetate.

Examples of alkyl halides include, but are not limited to, ethyl2-bromo-2-phenylacetate, dodecyl 2-bromoisobutyrate, ethyl2-bromoisobutyrate, ethyl 2-bromopropionate, 2-hydroxyethyl2-bromoisobutyrate, octadecyl 2-bromoisobutyrate,2-(2-bromoisobutyryloxy)ethyl methacrylate, 1-bromoethylbenzene,2-bromoisobutanoic acid N-hydroxysuccinimide ester, 2-bromoisobutyricanhydride, 2-azidoethyl 2-bromoisobutyrate,bis[2-(2′-bromoisobutyryloxy)ethyl]disulfide, andbis[2-(2-bromoisobutyryloxy)undecyl] disulfide.

In certain embodiments, the polymerization involves transfer radicalpolymerization (ATRP). In certain embodiments, the ATRP uses a catalyst.In certain embodiments, the catalyst is a metal catalyst. In certainembodiments, the polymerization involves addition-fragmentation chaintransfer (RAFT) polymerization.

In addition to the acrylate monomers incorporated into the polymersdescribed herein, one or more other monomers may be incorporated viapolymerization to form a copolymer (e.g., a block copolymer describedherein). In certain embodiments, one or more other monomers are selectedfrom the group consisting of styrenes, methacrylates, acrylates,acrylamides, vinyl halides, vinyl alcohols, vinyl esters, and vinylamides. Further examples of polymers that may be incorporated include,but are not limited to, polyvinyl polymers (e.g., polyvinyl chloride),polyethylenes (e.g., polyethylene, polytetrafluoroethylene),polypropylenes, polyacetylenes, polyethers (e.g., polyethylene glycol,polyoxymethylene, polypropylene glycol, polytetramethylene glycol,poly(ethyl ethylene) phosphate, poly(oxazoline)), polyamines, polyesters(e.g., polyglycolic acid, polylactic acid, poly(lactic-co-glycolicacid), polycaprolactone, polyhydroxyalkanoate, polyhydroxybutryate,polyethylene adipate, polybutylene succinate,poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polysilanes, polysiloxanes(e.g., polydimethylsiloxane), polyacrylates (e.g., polymethacrylate,poly(n-butyl acrylate), poly(tert-butyl acrylate)), polystyrenes,polylactides (e.g., polylactic acid), polyamino acids, polypeptides,polyamides, polyacrylamides (e.g., polymethylacrylamide), andpolysaccharides.

EXAMPLES

Poly(meth)acrylate BCPs can be derivatized to achieve higher χparameters. Herein, it is presented in the first place that using LiAH₄,the block copolymers of poly(methyl methyacrylate) (PMMA) or poly(methylacrylate) (PMA) can be reduced in a controlled manner. The microphaseseparation between pristine BCP samples and the reduction products iscompared to demonstrate the massive increase in χ values. Smalld-spacing was achieved. It is envisioned that this work will demonstratean important strategy for the convenient synthesis of high χ BCPs toapproach the downscaling limit. A generic representation of thesynthesis of PiBOH and PPOH polymers is shown in Scheme 1.

The work started with reducing the BCPs of methyl methacrylate or methylacrylate in a controlled manner (Scheme 1). The pristine poly(methylmethacrylate)-b-polystyrene (PMMA-b-PS), poly(methylacrylate)-b-polystyrene (PMA-b-PS), and poly(methylacrylate)-b-poly(tert-butylstyrene) (PMA-b-PtBS) were synthesized withnarrow molecular weight (MW) distribution, with either atom transferradical polymerization (ATRP) or reversible addition-fragmentation chaintransfer radical polymerization (RAFT) technique. It is noted here that,for RAFT synthesized BCPs, the trithiocarbonate end groups were removedbefore LiAH₄ reduction, using the method reported by: Rizzardo et al.“Thiocarbonylthio End Group Removal from RAFT-Synthesized Polymers by aRadical-Induced Process”, J. Polym. Sci. PartA Polym. Chem. 2009, 47(23), 6704-6714. This was based on the consideration that thetrithiocarbonate end-groups would be reduced into thiol, which couldlead to end-linking reactions. Then the BCPs were dissolved in THF anddegassed by sparging with N₂, followed by dropwise addition onto LiAlH₄.Upon refluxing overnight, the reaction was quenched via adding excesswater. To remove the inorganic side products, the resultant precipitatewas boiled at 100° C. with first HCl solution (3˜5 M, 2*30 mL per gramof polymer) and then DI-water (5*30 mL per gram of polymer). Afterdrying, it was found that in the Fourier transformed-infrared spectra(Supporting Information), the peak corresponding to the carbonylstretching, originally at 1727 cm⁻¹, disappeared, which confirmed theelimination of ester groups. At the same time, the absence of signals atδ>160 ppm in ¹³C NMR proved that aldehyde, acid, or amide, were notgenerated in this reaction. The MW distributions were measured using gelpermeation chromatography (GPC) with 0.025M LiBr in DMF as the eluent.The low D values were retained, proving the suppression of backbonedegradation. In the GPC traces (FIG. 1 ), the emerging of the smallshoulder of high molecular weight species is likely due to hydrogenbonding induced aggregation. By elemental analysis on representativesamples, only trace amount of salt can be detected (<0.5 wt % Clcontent). These confirmed the controlled synthesis ofpoly(hydroxyisobutylene)-b-polystyrene (PiBOH-b-PS),poly(hydroxypropylene)-b-polystyrene (PPOH-b-PS), andpoly(hydroxypropylene)-b-poly(tert-butylstyrene) (PPOH-b-PtBS), assummarized in Table 1. Using differential scanning calorimetry, theglass transition of PiBOH was detected around 100° C., while the Tg ofPPOH was measured to be 65° C.

TABLE 1 Summary of Block Copolymers Investigated. BCP Method^(a) DP_(OH)^(b) DP_(S) ^(b) Ð^(c) N^(d) f_(OH) ^(e) (%) Phase^(f) d^(g) (nm)PiBOH₁₈₅-b-PS₁₆₈ ATRP 185 168 1.16 (1.29) 401.9 40.7 LAM 41.89PiBOH₁₈₅-b-PS₁₄₅ ATRP 185 145 1.35 (1.37) 369.5 44.3 LAM 46.20PiBOH₁₈₅-b-PS₁₀₀ ATRP 185 100 1.31 (1.33) 306.0 53.5 LAM 35.70PiBOH₁₂₀-b-PS₁₂₂ ATRP 120 122 1.28 (1.24) 279.7 38.0 LAM 42.74PiBOH₁₈₅-b-PS₅₁ ATRP 185 51 1.31 (1.35) 237.0 71.7 HEX 26.10PiBOH₈₄-b-PS₅₁ ATRP 84 51 1.24 (1.11) 147.9 50.5 LAM 22.52PiBOH₆₅-b-PS₄₉ RAFT-ER 65 49 1.28 (1.29) 128.3 45.0 LAM 21.08PiBOH₆₅-b-PS₄₃ RAFT-ER 65 43 1.22 (1.30) 119.8 48.2 LAM 19.27PiBOH₆₅-b-PS_(36.5) RAFT-ER 65 36.5 1.24 (1.22) 110.7 52.3 LAM 18.37PiBOH₆₅-b-PS_(27.5) RAFT-ER 65 27.5 1.22 (1.22) 98.0 59.1 LAM 17.75PiBOH₃₀-b-PS₄₃ RAFT-ER 30 43 1.19 (1.10) 88.9 30.1 HEX 12.57PiBOH₃₀-b-PS_(28.5) RAFT-ER 30 28.5 1.25 (1.26) 68.5 39.2 LAM 12.32PiBOH₂₁-b-PS_(23.4) RAFT-ER 21 23.4 1.16 (1.24) 53.4 35.4 HEX 9.24PiBOH₂₁-b-PS₁₄ RAFT-ER 21 14 1.18 (1.15) 40.1 47.3 LAM 7.66PiBOH₁₆-b-PS₁₄ RAFT-ER 16 14 1.31 (1.20) 35.7 40.6 LAM 7.18PiBOH₁₆-b-PS₁₃ RAFT-ER 16 13 1.25 (1.15) 34.3 46.2 DIS N.A.PiBOH_(10.8)-b-PS_(12.6) RAFT-ER 10.8 12.6 1.21 (1.15) 29.1 37.5 DISN.A. PPOH_(11.7)-b-PS₂₁ ATRP 11.7 21 1.08 (1.05) 38.1 22.3 HEX 7.27(7.29) PPOH_(11.7)-b-PS_(18.4) ATRP 11.7 18.4 1.06 (1.04) 34.4 24.7 HEX7.51 (7.52) PPOH_(11.7)-b-PS_(14.5) ATRP 11.7 14.5 1.08 (1.06) 28.9 29.4HEX 7.27 (7.29) PPOH_(11.7)-b-PtBS_(15.2) ATRP 11.7 15.2 1.06 (1.02)44.6 19.1 BCC (7.11) PPOH_(8.6)-/b-PtBS_(13.8) ATRP 8.6 13.8 1.06 (1.03)39.2 16.4 ODT (6.68) PPOH_(11.7)-b-PtBS_(11.3) ATRP 11.7 11.3 1.06(1.02) 35.3 24.1 HEX (6.53) PPOH_(9.1)-b-PtBS₈ ATRP 9.1 8 1.12 (1.01)25.8 26.3 DIS N.A. For Table 1 ^(a)The technique utilized in pre-polymersynthesis before LiAlH₄ reduction, either ATRP or RAFT-ER (RAFT with theend-group removal process). ^(b)DP_(OH) and DP_(S) are degrees ofpolymerization for the polyhydroxy and polystyrenic blocks,respectively, which are calculated by end-group analysis using ¹H NMRspectra. ^(c)Measured by GPC. The values in the parentheses are on thepre-polymer before LiAlH₄ reduction (for RAFT-ER synthesized BCPs, thevalues were obtained after the removal of trithiocarbonate groups).^(d)Calculated using a reference volume of 118 Å³, based on the densityof PiBOH, PS, and PtBS being 1.15, 1.04, and 0.95 g/cm³, respectively,while the density of PPOH being estimated to be 1.22 g/cm³. ^(e)Volumefraction of polyhydroxy block domains. ^(f)Morphologies observed uponthermal annealing. HEX denotes hexagonally packed cylinders, LAM denoteslamellae, BCC is for spheres with body centered cubic packing, DISstands for disordered phase, while ODT means the sample was inorder-disorder transition state. ^(g)The d-spacing achieved by thermalannealing at 134 ± 1° C., and the values in the parentheses are at 179 ±1° C..

For Table 1: ^(a)The technique utilized in pre-polymer synthesis beforeLiAlH₄ reduction, either ATRP or RAFT-ER (RAFT with the end-groupremoval process). ^(b)DP_(OH) and DP_(s) are degrees of polymerizationfor the polyhydroxy and polystyrenic blocks, respectively, which arecalculated by end-group analysis using ¹H NMR spectra. ^(c)Measured byGPC. The values in the parentheses are on the pre-polymer before LiAlH₄reduction (for RAFT-ER synthesized BCPs, the values were obtained afterthe removal of trithiocarbonate groups). ^(d)Calculated using areference volume of 118 Å³, based on the density of PiBOH, PS, and PtBSbeing 1.15, 1.04, and 0.95 g/cm³, respectively, while the density ofPPOH being estimated to be 1.22 g/cm³. ^(e)Volume fraction ofpolyhydroxy block domains. ^(f)Morphologies observed upon thermalannealing. HEX denotes hexagonally packed cylinders, LAM denoteslamellae, BCC is for spheres with body centered cubic packing, DISstands for disordered phase, while ODT means the sample was inorder-disorder transition state. ^(g)The d-spacing achieved by thermalannealing at 134±1° C., and the values in the parentheses are at 179±1°C.

To investigate the bulk morphologies, the BCPs were applied to thermalannealing at designated temperatures for at least 12 hours and thenquenched to room temperature to achieve equilibrated morphologies. Byinvestigating the small angle X-ray scattering (SAXS) pattern achievedusing synchrotron beam, the morphologies of the BCPs before and afterreduction were compared. In FIG. 2 , the top two traces denotePMMA₁₈₅-b-PS₁₆8 (after end-group removal) and PiBOH₁₈₅-b-PS₁₆₈. Bothtraces show peaks with a position ratio of 1:2:3, indicating lamellarmorphologies. However, it was observed that the d-spacing (d, calculatedby d=2π/q*, where q* is the primary peak position) was increased from 25nm to 41.9 nm upon converting the PMMA block into PiBOH. This is likelya result of the largely increased χ value, since mean field theorysuggests that d-spacing rises monotonically with increased χ. See, e.g.,Bates et al. “Block Copolymers—Designer Soft Materials”, Phys. Today1999, 52 (2), 32-38. Note that the ordering seems to be poor, which canprobably be attributed to the slow ordering kinetics due to hydrogenbonding within PiBOH domains. The bottom half of FIG. 2 shows thatPMMA₆₅-b-PS₄₉ was in disordered state, while PiBOH₆₅-b-PS₄₉ exhibitedhighly ordered lamellar morphologies, since the peak positions were in aratio being 1:2:3:4. The pristine BCP was also blended with 10 wt % LiCland then annealed thermally. However, the salt/polymer complex showed nosign of ordered microphases. This assures that the difference in phasebehavior is a consequence of the chemical structures rather than thetrace residual salt. Considering the high ratio of hydroxyl groups overresidual Cl⁻ (>60), it is expected that residual salt should have verylimited effect on the segregation strength. The suppression of thesecond order peak in PiBOH₆₅-b-PS₄₉ is likely a consequence of thesymmetry in volume fractions. The d-spacing is found to be 20.8 nm. Sofar, these two comparisons have demonstrated that PiBOH-b-PS has asignificantly enhanced χ interaction parameter comparing with PMMA-b-PS.

A series of PiBOH-b-PS samples were investigated on their morphologies.Most of these BCPs, as shown in Table 1, have volume fractions close to50%, and they displayed lamellar morphologies as confirmed by SAXS. Forexample, PiBOH₈₄-b-PS₅₁ is shown in FIG. 3 a , where ordered lamellae(d=22.52 nm) can be observed from the peaks with a position ratio of1:2:3 in the SAXS pattern. Using TEM, layered structures with an averagecenter-to-center distance being 20 nm were displayed, which wasconsistent with the SAXS measurement. The volume fraction was also tunedto achieve other morphologies. For example, PiBOH₂₁-b-PS_(23.4) with avolume fraction of PiBOH being 38.6%, showed peaks at a position ratioof 1:√3:√4, indicating hexagonally packed PiBOH cylinders. In contrast,PiBOH₁₈₅-b-PS₅₁ (f_(OH)=71.7%) exhibited peak positions being1:√4:√7:√12, which is likely the inverse cylindrical morphologies.

Then, the morphologies of BCPs with various N values were investigated.The shortest PiBOH-b-PS sample that showed a sharp peak (FIG. 3 b ) at134° C. had an N of 35.7. The spacing is found to be 7.18 nm. Base onthe volume fractions, it is expected to exhibit a lamellar morphology,although the higher order peaks are missing, which is attributed to thenearly symmetric volume fractions. To confirm the ordered microphaseseparation, PiBOH₁₆-b-PS₁₄ was annealed at 150° C., and the peakbroadened significantly, which was a sign of entering the disorderphase. Increasing the annealing temperatures led to further broadening(FIG. 3 b ). This indicated that the BCP passed the order-disordertransition between 134° C. and 150° C., and the χ_(eff)N value (χ_(eff)for effective χ parameter) at 134° C. is only slightly higher than 10.5.

In contrast, the polymer with N=34.3 (PiBOH₁₆-b-PS₁₃) showed only abroad peak in the SAXS pattern. This suggests that the χ_(eff)N valuecrossed the critical point of being 10.5, when N changes from 35.7 to34.3. So, one can estimate the effective χ parameter (χ_(eff)) to be 0.3at 134° C. This gives PiBOH₁₆-b-PS₁₄ a χ_(eff)N value of 10.7, which isin good consistency with the previously observed order-disordertransition (ODT). Comparing with PMMA-b-PS at similar conditions(χ_(eff)=0.03, with a reference volume of 118 Å³ at 150° C.), it isdemonstrated here that the χ_(eff) value can be increased by one orderof magnitude using a basic organic reaction that is approachable in anychemistry labs. See, e.g., Koo et al. “Directed Self-Assembly of BlockCopolymers in the Extreme: Guiding Microdomains from the Small to theLarge”, Soft Matter 2013, 9 (38), 9059; Russell et al. “TemperatureDependence of the Interaction Parameter of Polystyrene and Poly (MethylMethacrylate)”, Macromolecules 1990, 23, 890-893. To further elucidatethe significance, here compare with the high χ_(eff) values reported inliterature that were determined using ODT. For example,poly(cyclohexylethylene)-b-poly(ethylene oxide) possesses a χ_(eff)being 0.22 at 150° C. and a reference volume of 118 Å³, while undersimilar conditions, polystyrene-b-polydimethylsiloxane,poly(cyclohexylethylene)-b-poly(methyl methacrylate), poly(tert-butylstyrene)-b-poly(2-vinylpyridine), and poly(methylmethacrylate)-b-polydimethylsiloxane were found to have χ_(eff) valuesbeing 0.11, 0.053, 0.11, and 0.24, respectively. See, e.g., Kennemur etal. “Sub-5 Nm Domains in OrderedPoly(cyclohexylethylene)-Block-Poly(methyl Methacrylate) Block Polymersfor Lithography,” Macromolecules 2014, 47 (4), 1411-1418; Andersen etal. “Surface Morphology of PS-PDMS Diblock Copolymer Films”, J. ElectronSpectros. Relat. Phenomena 2001, 121 (1-3), 93-110. Various χ valueswere reported on poly(4-vinylpyridine)/polystyrene pair depending on thetesting methodology, while ODT has not been used. However, from the workby Chang Dae Han et al., it is estimated that the χ_(eff) (ODT) valueshould be lower than 0.34, when the temperature and reference volumebeing 160° C. and 118 Å³. See, e.g., Zha et al. “Origin of theDifference in Order-Disorder Transition Temperature betweenPolystyrene-Block-poly(2-Vinylpyridine) andPolystyrene-Block-poly(4-Vinylpyridine) Copolymers”, Macromolecules2007, 40 (6), 2109-2119. On poly(3,4-dihydroxystyrene)-b-polystyrene,the χ value was computed to be ˜0.7 by fitting the SAXS profiles withLeibler theory, while the χ_(eff) value is reduced to be between 0.37and 0.50 when merely using the molecular weights below and above ODT(the temperature and reference volume being 170° C. and 118 Å³,respectively). Similarly,poly(trimethylsilylstyrene)-b-poly(D,L-lactide) was investigated toreveal its χ_(eff) value being 0.42 at 140° C. using the absolutescattering intensity. See, e.g., Cushen et al. “Thin Film Self-Assemblyof Poly(trimethylsilylstyrene-B-D,L-Lactide) with Sub-10 Nm Domains”,Macromolecules 2012, 45 (21), 8722-8728. However, it was re-estimatedthe χ_(eff) (ODT) to be no larger than 0.35. So far, it has beendemonstrated that the χ_(eff) value obtained on PiBOH-b-PS is amongstthe highest.

To better understand how d is affected by N, the d values of lamellarsamples are plotted against N in FIG. 4 in a log-log manner. Fitting thedata linearly results in a scaling relationship of d˜N^(δ) with R²=0.98indicating successful regression. Then, a value of δ=0.77 can beextracted, which is larger than the value (⅔) predicted by strongsegregation theory. See, e.g., Hashimoto et al. “Domain-BoundaryStructure of Styrene-Isoprene Block Copolymer Films Cast from Solution,4. Molecular-Weight Dependence of Lamellar Microdomains”, Macromolecules1980, 13 (5), 1237-1247; Leibler, L. “Theory of Microphase Separation inBlock Copolymers”, Macromolecules 1980, 13 (6), 1602-1617. It suggeststhat these BCP chains adopted relatively stretched conformation, andthis phenomenon has been observed in a few reports, however, not yetfully understood. See, e.g., Sunday et al. “Characterizing the InterfaceScaling of High χ Block Copolymers near the Order-Disorder Transition”,Macromolecules 2017; Papadakis et al. “Identification of anIntermediate-Segregation Regime in a Diblock Copolymer System”,Europhys. Lett. 1996, 36 (4), 289-294; Almdal et al. “Gaussian-toStretched-Coil Transition in Block Copolymer Melts”, Phys. Rev. Lett.1990, 65 (9), 1112-1115.

To access even smaller spacing values, the PPOH-b-PS samples wereexamined. Annealed at 134° C., PPOH_(11.7)-b-PS₂₁ andPPOH_(11.7)-b-PS_(18.4) exhibited peaks at position ratios of 1:√3: √5indicating hexagonal morphologies, and d-spacing values being 7.51 and7.38 nm, respectively. With an N value of 28.9, PPOH_(11.7)-b-PS_(14.5)also had a hexagonal morphology (d=7.27 nm), since a set of sharp peakswith a position ratio of 1:√3:√4:√5 were observed in the SAXS pattern(FIG. 5 ). This indicates that PPOH-b-PS block copolymers should have aχ_(eff) being at least as high as 0.37.

Similarly, the PPOH-b-PtBS samples were thermally annealed at 179° C.(due to the Tg of PtBS). Interestingly, PPOH_(11.7)-b-PtBS_(15.2),having N=44.6 and f_(OH)=19.1%, displayed a set of peaks with a positionratio of 1:√2:√3:√4:√5 (FIG. 5 ). This indicates a body centered cubicpacking of spherical morphology with d=7.11 nm. This is among thesmallest d-spacing reported on spherical morphologies. At such atemperature, order-disorder transition was detected onPPOH_(8.6)-b-PtBS_(13.8) (N=39.2, f_(OH)=16.4%), since a coexistence ofa broad peak and a sharp first order peak was observed (SupportingInformation). The smallest d in this work is 6.53 nm, observed onPPOH_(11.7)-b-PtBS_(11.3) (N=35.3, f_(OH)=24.1%, FIG. 5 ). It displayeda series of sharp peaks at a position ratio of 1:√3:√5 (the peak at √4q*is missing because being cancelled by the form factor), and thus can bedetermined to be cylindrical morphology. It is estimated that thecylinder diameter is ˜4.1 nm. This is comparable with the smallestd-spacing (6.5 nm) and feature size (˜4 nm) achieved experimentally sofar on cylindrical morphologies.

In conclusion, this work demonstrated that LiAlH₄ can be used to reduceblock copolymer of PMMA or PMA in a controlled manner. The change inchemical structure endows the new BCPs much enhanced χ_(eff) interactionparameters, which allows them to form well-ordered morphologies with avery short chain length, i.e. N=28.5 in this work. The smallest spacingachieved in this work is 7.18 nm for lamellae, 6.53 nm for hexagonallypacked cylinders, and 7.11 nm for body centered cubic morphologies.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein.

It is also noted that the terms “comprising” and “containing” areintended to be open and permits the inclusion of additional elements orsteps. Where ranges are given, endpoints are included. Furthermore,unless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or sub-range withinthe stated ranges in different embodiments of the invention, to thetenth of the unit of the lower limit of the range, unless the contextclearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A method of preparing a block copolymer of theformula:

the method comprising reducing an original block copolymer of theformula:

wherein: R⁴ is hydrogen or C₁₋₆ alkyl; R¹, R², and R³ are eachindependently hydrogen or C₁₋₆ alkyl; T¹ and T² are each independently aterminal group selected from hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substituted acyl; R⁵,R⁶, and R⁷ are each independently hydrogen or C₁₋₆ alkyl; R⁸ isoptionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substituted acyl; or R⁸is a polymer; and n and m are each independently an integer from 1 to2000, inclusive.
 2. The method of claim 1, wherein the original blockcopolymer is of the formula:


3. The method of claim 2, wherein the original block copolymer is of theformula:

wherein: each instance of R^(8a) is independently halogen, —CN, —NO₂,—N₃, optionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —OR^(O),—SR^(S), or —N(R^(N))₂; each instance of R^(O) is independentlyhydrogen, optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, oran oxygen protecting group; each instance of R^(N) is independentlyhydrogen, optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, ora nitrogen protecting group; optionally wherein two R^(N) attached tothe same nitrogen atom are joined together with the intervening atoms toform optionally substituted heterocyclyl or optionally substitutedheteroaryl; each instance of R^(S) is independently hydrogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, or a sulfurprotecting group; and p is 0, 1, 2, 5, 4, or
 5. 4. The method of claim1, wherein the step of reducing is carried out in the presence of ahydride donor.
 5. The method of claim 1, wherein the step of reducing iscarried out in the presence of a reducing reagent selected from thegroup consisting of lithium aluminum hydride (LiAlH₄), hydrogen gas,sodium amalgam, sodium-lead alloy, diborane, sodium borohydride,dithionates, thiosulfates, hydrazine, diisobutylaluminium hydride(DIBAL), oxalic acid, formic acid, ascorbic acid, lithiumtriethylborohydride, diborane, borane-tetrahydrofuran, borane-dimethylsulfide, samarium, sodium bis(2-methoxyethoxy)aluminium hydride, sodiumtriacetoxyborohydride, and zinc.
 6. The method of claim 4, wherein thehydride donor is lithium aluminum hydride (LiAlH₄).
 7. The method ofclaim 1 further comprising polymerizing two or more monomers to producethe original block copolymer, wherein at least one monomer is anacrylate of the formula:


8. The method of claim 7, wherein the polymerization step is apolymerization selected from the group consisting of living radicalpolymerization, reversible-deactivation radical polymerization, atomtransfer radical polymerization (ATRP), nitroxide mediated radicalpolymerization (NMP), and reversible addition-fragmentation chaintransfer (RAFT) polymerization.
 9. The method of claim 7, wherein thepolymerization uses an iniferter, initiator, or chain transfer agent.10. The method of claim 9, wherein the iniferter, initiator, or chaintransfer agent is selected from the group consisting of dithiobenzoates,trithiocarbonates, dithiocarbamates, xanthates, and alkyl halides. 11.The method of claim 10, wherein the dithiobenzoate is selected from thegroup consisting of benzyl benzodithioate, cyanomethyl benzodithioate,4-cyano (phenylcarbonothioylthio)pentanoic acid,4-cyano-4-(phenylcarbonothioylthio)pentanoic acid N-succinimidyl ester,2-cyano-2-propyl benzodithioate, 2-cyano-2-propyl 4-cyanobenzodithioate,ethyl 2-(4-methoxyphenylcarbonothioylthio)acetate, ethyl2-methyl-2-(phenylthiocarbonylthio)propionate, ethyl2-(phenylcarbonothioylthio)-2-phenylacetate, ethyl2-(phenylcarbonothioylthio)propionate, 1-(methoxycarbonyl)ethylbenzodithioate, 2-(4-methoxyphenylcarbonothioylthio)ethanoic acid,2-nitro-5-(2-propynyloxy)benzyl4-cyano-4-(phenylcarbonothioylthio)pentanoate,2-(phenylcarbonothioylthio)propanoic acid, and 2-phenyl-2-propylbenzodithioate.
 12. The method of claim 10, wherein the trithiocarbonateis selected from the group consisting of3,5-bis(2-dodecylthiocarbonothioylthio-1-oxopropoxy)benzoic acid,2-cyanobutan-2-yl 4-chloro-3,5-dimethyl-1H-pyrazole-1-carbodithioate,2-cyanobutanyl-2-yl 3,5-dimethyl-1H-pyrazole-1-carbodithioate,4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid,4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanol, cyanomethyl(3,5-dimethyl-1H-pyrazole)-carbodithioate, cyanomethyl dodecyltrithiocarbonate, cyanomethyl [3-(trimethoxysilyl)propyl]trithiocarbonate, 2-cyano-2-propyl dodecyl trithiocarbonate,S,S-dibenzyl trithiocarbonate, 2-(dodecylthiocarbonothioylthio)propionicacid, 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid3-azido-1-propanol ester,2-(dodecylthiocarbonothioylthio)-2-methylpropionic acidN-hydroxysuccinimide ester,2-(dodecylthiocarbonothioylthio)-2-methylpropionic acidpentafluorophenyl ester, phthalimidomethyl butyl trithiocarbonate,methyl 2-(dodecylthiocarbonothioylthio)-2-methylpropionate,2,2′-(thiocarbonylbis(sulfanediyl))bis(2-methylpropanoic acid), dibenzyl2,2′-(thiocarbonylbis(sulfanediyl))bis(2-methylpropanoate), dibenzyl2,2′-(thiocarbonylbis(sulfanediyl))dipropionate, and2-(((dodecylthio)carbonothioyl)thio)propanoic acid.
 13. The method ofclaim 10, wherein the dithiocarbamate is selected from the groupconsisting of benzyl 1H-pyrrole-1-carbodithioate, cyanomethyldiphenylcarbamodithioate, cyanomethyl methyl(phenyl)carbamodithioate,cyanomethyl methyl(4-pyridyl)carbamodithioate, 2-cyanopropan-2-ylN-methyl-N-(pyridin-4-yl)carbamodithioate, methyl2-[methyl(4-pyridinyl)carbamothioylthio]propionate, and1-succinimidyl-4-cyano-4-[N-methyl-N-(4-pyridyl)carbamothioylthio]pentanoate.14. The method of claim 10, wherein the xanthate is selected from thegroup consisting of ethyl 2-(((ethylthio)carbonothioyl)thio)propanoate,methyl (4-methoxyphenoxy)carbonothioylsulfanyl acetate, methyl(methoxycarbonothioyl)sulfanyl acetate, methyl(ethoxycarbonothioyl)sulfanyl acetate, and methyl(isopropoxycarbonothioyl)sulfanyl acetate.
 15. The method of claim 10,wherein the alkyl halide is selected from the group consisting of ethyl2-bromo-2-phenylacetate, dodecyl 2-bromoisobutyrate, ethyl2-bromoisobutyrate, ethyl 2-bromopropionate, 2-hydroxyethyl2-bromoisobutyrate, octadecyl 2-bromoisobutyrate,2-(2-bromoisobutyryloxy)ethyl methacrylate, 1-bromoethylbenzene,2-bromoisobutanoic acid N-hydroxysuccinimide ester, 2-bromoisobutyricanhydride, 2-azidoethyl 2-bromoisobutyrate,bis[2-(2′-bromoisobutyryloxy)ethyl]disulfide, andbis[2-(2-bromoisobutyryloxy)undecyl] disulfide.
 16. The method of claim7, wherein one or more other monomers are selected from the groupconsisting of styrenes, acrylamides, vinyl halides, vinyl alcohols,vinyl esters, and vinyl amides.
 17. The method of claim 7, wherein thepolymerization involves transfer radical polymerization (ATRP).
 18. Themethod of claim 1, wherein the original block copolymer is poly(methylmethacrylate)-b-polystyrene (PMMA-b-PS), and the block copolymer ispoly(hydroxyisobutylene)-b-polystyrene (PiBOH-b-PS).
 19. The method ofclaim 1, wherein the original block copolymer is poly(methylacrylate)-b-polystyrene (PMA-b-PS), and the block copolymer ispoly(hydroxypropylene)-b-polystyrene (PPOH-b-PS).
 20. The method ofclaim 1, wherein the original block copolymer is poly(methylacrylate)-b-poly(tert-butylstyrene) (PMA-b-PtBS), and the blockcopolymer is poly(hydroxypropylene)-b-poly(tert-butylstyrene)(PPOH-b-PtBS).
 21. A method of using a block copolymer prepared by themethod of claim 1, the method comprising substituting the —OH groups ofthe block copolymer to form a block copolymer of the formula:

wherein: R^(A) is —OR^(O), —SR^(S), —N(R^(N))₂, or substitutedphosphorous; R^(O) is optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, or an oxygen protecting group; each instance of R^(N)is independently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, or a nitrogen protecting group; optionally wherein twoR^(N) attached to the same nitrogen atom are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl; and R^(S) is hydrogen, optionallysubstituted alkyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, or a sulfurprotecting group.